rs147442301

Positions:

chr12-120727143-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The ENST00000242592.9(ACADS):c.164C>T(p.Pro55Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000223 in 1,614,154 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

ACADS
ENST00000242592.9 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 6.93

Variant links:

Genes affected

ACADS (HGNC:90): (acyl-CoA dehydrogenase short chain) This gene encodes a tetrameric mitochondrial flavoprotein, which is a member of the acyl-CoA dehydrogenase family. This enzyme catalyzes the initial step of the mitochondrial fatty acid beta-oxidation pathway. Mutations in this gene have been associated with short-chain acyl-CoA dehydrogenase (SCAD) deficiency. Alternative splicing results in two variants which encode different isoforms. [provided by RefSeq, Oct 2014]

ACADS links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.957

PP5

Variant 12-120727143-C-T is Pathogenic according to our data. Variant chr12-120727143-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 30611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACADS	NM_000017.4 linkuse as main transcript	c.164C>T	p.Pro55Leu	missense_variant	2/10	ENST00000242592.9	NP_000008.1
ACADS	NM_001302554.2 linkuse as main transcript	c.164C>T	p.Pro55Leu	missense_variant	2/10		NP_001289483.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
ACADS	ENST00000242592.9 linkuse as main transcript	c.164C>T	p.Pro55Leu	missense_variant	2/10	1	NM_000017.4	ENSP00000242592	P1
ACADS	ENST00000411593.2 linkuse as main transcript	c.164C>T	p.Pro55Leu	missense_variant	2/10	2		ENSP00000401045
ACADS	ENST00000539690.1 linkuse as main transcript	n.276C>T		non_coding_transcript_exon_variant	2/3	2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000579

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000358

AC:

AN:

251496

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000489

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000226

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000781

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152262

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000580

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000340

ExAC

AF:

0.0000659

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Deficiency of butyryl-CoA dehydrogenase

Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM2_Supporting+PM3_VeryStrong+PP3_Strong -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 28, 2022	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 55 of the ACADS protein (p.Pro55Leu). This variant is present in population databases (rs147442301, gnomAD 0.05%). This missense change has been observed in individuals with short chain acyl-CoA dehydrogenase deficiency (PMID: 18951053, 20376488, 27938594, 28018444). ClinVar contains an entry for this variant (Variation ID: 30611). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ACADS protein function. Experimental studies have shown that this missense change affects ACADS function (PMID: 20376488). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2010	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 14, 2018	The ACADS c.164C>T (p.Pro55Leu) missense variant has been reported in four studies in which it is found in a total of six individuals with SCAD deficiency, including in one with the variant in a homozygous state and in five in a compound heterozygous state. All individuals carrying the variant were diagnosed with SCAD deficiency through newborn screening and were clinically asymptomatic, even during follow-up in childhood (Jethva and Ficicioqlu 2008; Shirao et al. 2010; An et al. 2016; Kim et al. 2016). In addition, Huang et al. (2016) reported the p.Pro55Leu variant in approximately 20% of 17 clinically asymptomatic Chinese children who were identified through newborn screening as having SCAD deficiency. Control data are unavailable for this variant, which is reported at a frequency of 0.00092 in the East Asian population of the Exome Aggregation Consortium. Shirao et al. (2010) performed in vitro testing of the variant and found that HEK293 cells that were transfected with the variant protein had 6.67% enzymatic activity compared to wild type. When the variant was co-transfected with wild type protein, 60-70% of normal enzymatic activity was observed. Based on the collective evidence, the p.Pro55Leu variant is classified as pathogenic for SCAD deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 09, 2023	Variant summary: ACADS c.164C>T (p.Pro55Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251496 control chromosomes. c.164C>T has been reported in the literature as a compound heterozygous genotype in settings of biochemically confirmed diagnosis/newborn screen for Short-chain acyl-CoA dehydrogenase (SCAD) deficiency (example, Shirao_2010, An_2016, Huang_2022). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Shirao_2010). The most pronounced variant effect results in <10% of normal SCAD enzymatic activity in-vitro. The following publications have been ascertained in the context of this evaluation (PMID: 28018444, 35193651, 20376488). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	research	Medical Laboratory Center, Huzhou Maternal and Child Health Hospital	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jul 31, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

D;D

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Uncertain

0.92

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Pathogenic

0.39

MetaRNN

Pathogenic

0.96

D;D

MetaSVM

Pathogenic

0.91

MutationAssessor

Pathogenic

4.8

H;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-8.7

D;D

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.99

D;D

Vest4

0.94

MVP

0.96

MPC

0.78

ClinPred

1.0

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.95

gMVP

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over